{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,31]],"date-time":"2026-10-31T07:14:33Z","timestamp":1793430873758,"version":"4.5.0"},"reference-count":38,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,2,26]],"date-time":"2025-02-26T00:00:00Z","timestamp":1740528000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell. Infect. Microbiol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>The increasing resistance of <jats:italic>Candida albicans<\/jats:italic> (<jats:italic>C. albicans<\/jats:italic>) to conventional antifungal drugs poses a great challenge to the clinical treatment of infections caused by this yeast. Drug combinations are a potential therapeutic approach to overcome the drug- resistance of <jats:italic>C. albicans<\/jats:italic>. This study explored the synergistic effects of amantadine hydrochloride (AMH) combined with azole antifungal drugs against drug-resistant <jats:italic>C. albicans in vitro<\/jats:italic> and <jats:italic>in vivo<\/jats:italic>.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>The <jats:italic>in vitro<\/jats:italic> sensitivity of <jats:italic>Candida<\/jats:italic> spp. to drugs was determined by the microdilution method. The effect of drugs on the efflux pump activity of <jats:italic>C.\u00a0albicans<\/jats:italic> was determined by the rhodamine 6G tracer method. The egg yolk agar plate method was used to determine the activity of extracellular phospholipase, a <jats:italic>C. albicans<\/jats:italic> virulence factor. The <jats:italic>Galleria mellonella<\/jats:italic> model\u00a0of\u00a0<jats:italic>C. albicans<\/jats:italic> infection was used to test the <jats:italic>in vivo<\/jats:italic> efficacy of the combination therapy.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p><jats:italic>In vitro<\/jats:italic> experiments showed that combinations of AMH with azole antifungal drugs had synergistic antifungal effects on planktonic cells of drug-resistant <jats:italic>C. albicans<\/jats:italic>, with fractional inhibitory concentration index values of &amp;lt;0.5. The <jats:italic>in vivo<\/jats:italic> synergistic effects and mechanism of drug combinations with AMH were further studied using fluconazole (FLC) as a representative azole antifungal drug. <jats:italic>In vivo<\/jats:italic>, <jats:italic>G. mellonella<\/jats:italic> larvae were used to evaluate the antifungal efficacy of AMH +FLC. AMH + FLC treatment increased the survival rate of larvae infected with drug-resistant <jats:italic>C. albicans<\/jats:italic> and reduced tissue invasion. Studies of the mechanism of synergy showed that AMH inhibited drug efflux pump activity in drug-resistant <jats:italic>C. albicans<\/jats:italic>, and that AMH + FLC synergistically inhibited early biofilms and the extracellular phospholipase activity of drug-resistant <jats:italic>C. albicans<\/jats:italic>.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>This study provides strong evidence that combinations of non-antifungal drugs and antifungal drugs can effectively overcome drug-resistant <jats:italic>C.\u00a0albicans<\/jats:italic> infection. Both AMH and FLC are FDA-approved drugs, eliminating concerns about safety. Our findings provide a foundation for further clinical antifungal research.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fcimb.2025.1455123","type":"journal-article","created":{"date-parts":[[2025,2,26]],"date-time":"2025-02-26T07:23:54Z","timestamp":1740554634000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":7,"title":["Synergistic antifungal effects and mechanisms of amantadine hydrochloride combined with azole antifungal drugs on drug-resistant Candida albicans"],"prefix":"10.3389","volume":"15","author":[{"given":"Xiuyun","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanyuan","family":"Zhi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ximeng","family":"Duan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xu","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Cui","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shicun","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,2,26]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2019.00214","article-title":"The still underestimated problem of fungal diseases worldwide","volume":"10","author":"Almeida","year":"2019","journal-title":"Front. 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